7-Hydroxyamino-1,4-benzodiazepines

ABSTRACT

Novel 1,4-benzodiazepine derivatives, substituted in the 7position with a hydroxyamino group or an alkylated or acylated derivative thereof, are disclosed together with processes for the preparation of these compounds. These novel benzodiazepines are useful as sedative, muscle relaxant an anti-convulsant agents.

United States Patent 1191 Fryer et al.

[ 7-HYDROXYAMlNO-l,4-

BENZODIAZEPINES [75] Inventors: Rodney lan Fryer, North Caldwell;

Armin Walser, West Caldwell, both of NJ.

[73] Assignee: Hoffmann-La Roche Inc., Nutley,

[22] Filed: Nov. 29, 1973 21 App]. No.: 420,118

[52] U.S. Cl. 260/239.3 D, 424/244 [51] Int. Cl C07d 53/06 [58] Field ofSearch 260/2393 D [56] References Cited UNITED STATES PATENTS 3,391,1387/1968 Archer et al 260/2393 D [4 1 Feb. 11, 1975 Primary Examiner-HenryR. Jiles Assistant Examiner-Robert T. Bond Attorney, Agent, orFirm-Samuel L. Welt; Bernard S. Leon 571 ABSTRACT 13 Claims, No Drawings7-HYDROXYAMINO l,4-BENZODIAZEPINES DETAILED DESCRIPTION OF THE INVENTIONThe present invention relates to novel l ,4-benzodiazepin-2-ones whichbear a hydroxyaminogroup or an alkylated or acylated derivative thereofin the 7- position. The invention further comprehends processes formaking these novel benzodiazepines.

More specifically, the compounds of the present invention are selectedfrom the group consisting of compounds of the formula 2 I R c n whereinR signifies lower alkyl, hydroxylower alkyl, cycloalkyl-lower alkyl,lower alkoxy-lower alkyl or dilower alkylaminolower alkyl; R signifieshydrogen or lower alkyl; R signifies hydrogen or halogen; R signifieshydrogen or lower alkyl; R signifies hydrogen as the group COR whereinR,- is lower alkyl or halolower alkyl and the pharmaceuticallyacceptable acid addition salts thereof.

As used herein the term lower alkyl either alone or in combinationrefers to straight and branched chain hydrocarbon groups containing from1 to 7, preferably from 1 to 4 carbon atoms such as for example, methyl,ethyl, propyl, isopropyl, isobutyl, butyl and the like. The termhalogen" refers to all four forms thereof, i.e. bromine, chlorine,fluorine and iodine. The term lower alkoxy designates straight orbranched chain saturated hydrocarbonoxy groups containing from 1 to 7carbon atoms preferably 1 to 4 carbon atoms such as methoxy, ethoxy,propoxy and the like. The term cycloalkyl refers to cycloalkyl groupscontaining from 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl,cyclopentyl and the like. The term halo-lower alkyl refers tohalogenated alkyl groups such as chloromethyl, di-chloromethyl,trifluoromethyl and the like.

Preferred among the compounds falling within the scope of formula Iabove are those wherein R and R signify hydrogen, ie. compounds of theformula 2 rm C N Ia i on wherein R R and'R are as described above,andthe pharmaceutically acceptable acid addition salts thereof.

Also preferred among the compounds of formula I above are those whereinR signifies hydrogen and R signifies the group COR R being as definedabove i.e. compounds of the formula wherein R R R and R.,- are asdescribed above, and the pharmaceuticallyacceptable acid addition saltsthereof.

Still another preferred class of compounds falling within the scope offormula I above are those wherein R signifies lower alkyl and Rsignifies the group COR R being as defined above, i.e. compounds of theformula C ll R -CO-l wherein R signifies lower alkyl and R R R and R areas described above, and the pharmaceutically acceptable acid additionsalts thereof.

Another class of compounds falling within the scope of formula I aboveare those wherein R signifies lower alkyl and R signifies hydrogen, i.e.compounds of the formula c R M 2 HP! C N wherein R R and R are asdescribed above, and the pharmaceutically acceptable acid addition saltsthereof.

When the R substituent signifies lower alkyl, methyl is preferred; whenR signifies hydroxy lower alkyl, hydroxyethyl is preferred; when Rsignifies lower alkoxy -lower alkyl, methoxymethyl is preferred; when Rsignifies cycloalkyl-lower alkyl, cyclopropylmethyl is preferred andwhen R, signifies di-lower alkyl amino lower alkyl, di-ethylamino ethylis preferred. When the R substituent is halogen it is preferably locatedin the ortho position of the S-phenyl ring and chlorine and fluorine arethe preferred halogen groups. The preferred lower alkyl group for the Rand R substituents is methyl, while the preferred 'halo lower alkylgroup for the R substituent is trifluoromethyl.

Representative of the compounds of formula I above arel,3-dihydro-7-hydroxyaminol -methoxymethyl-5- phenyl-2I-l-1,4-benzodiazepin-2-one; 1,3-dihydro-7- (N-hydroxyacetamino)- 1-methoxymethyl- S-phenyl-ZH-l ,4-benz odiazepin-2-one; 1,3-dihydro-7-(N-methoxyacetamino)-l -methoxymethyl-5-phenyl- 2H-l,4-benzodiazepin-2-one and 1,3-dihydro-7-methoxyamino-l-methoxymethyl-5-phenyl-2H-l,4- benzodiazepin-Z-one.

The 7-hydroxyaminobenzodiazepines of formula la above are prepared bythe selective reduction of the corresponding 7-nitrobenzodiazepin-2-oneof the formula wherein R through R are as described above.

The 7-nitrobenzodiazepine derivatives of formula II above are knowncompounds or can be prepared in ployed are alcohols such as methanol,ethanol and the like, water, ethers such as tetrahydrofuran,hydrocarbons such as hexane and the like, chlorinated hydrocarbons suchas chloroform, methylenechloride and the like, acetone,dimethylformamide and dimethylsulfoxide. Temperature is not critical tothis process aspect, so that temperatures above or below roomtemperature can be employed with room temperature being preferred.

The compounds of formula lb above can be prepared by the acylation ofthe 7- hydroxyaminobenzodiazepines of formula la. This acylation canbeeffected by treating the compound of formula la with a suitableacylating agent.

Representative of the acylating agents that can be employed for thepurposes of the present invention are acid anhydrides, such as aceticanhydride, trifluoroacetic anhydride and the like and acid halides suchas acetyl chloride. This acylation reaction is preferably effected inthe presence of an acid acceptor such as an inorganic or organic basefor example, pyridine or sodium carbonate. It is also preferable toeffect this reaction in the presence of-an inert organic solvent.Suitable solvents include halogenated hydrocarbons such as methylenechloride, hydrocarbons such as hexane and the like, ethers such astetrahydrofuran, dimethylformamide, dimethylsulfoxide and ethyl acetate.Tem- 2 III OCOR wherein R, through R and R are as described above. Ifthe diacylated product is obtained, it can readily be converted to thedesired monoacyl product of formula lb by the selective cleavage of theO-acyl group to yield the hydroxy group. The selective cleavage isaccomplished by selective hydrolysis, for example, by treating thedi-acylated product with an alkalimetal hydroxide for example, sodiumhydroxide.

The compounds of formula lc above are prepared by the alkylation of thehydroxamic acid derivative of formula lb. This conversion is effectedemploying standard alkylating techniques. Representative of thealkylating agents that can be employed are alkyl/halides such asmethylchloride or methyliodide, alkyl sulphates such as methylsulphateand the like and diazoalkanes such as diazomethane and the like. Incarrying out this alkylation reaction, it is preferable to first formthe sodium salt of the hydroxamic acid of formula lb. This can beaccomplished by treating the hydroxamic acid with a reagent such assodium hydroxide, sodium hydride, sodium alcoholate and the like. It isexpedient to effect this alkylation reaction in the presence of an inertorganic solvent. Representative of the solvents that can be employed arehydrocarbons such as hexane, halogenated hydrocarbons such as methylenechloride, alcohols such as methanol, ethanol and the like, ethers suchas tetrahydrofuran, dimethylformamide and dimethylsulfoxide. Temperatureis not critical to this process aspect so that temperatures above orbelow room temperature can be employed with room temperature beingpreferred.

The compound of formula 1 above wherein R signifies lower alkyl and Rsignifies hydrogen can be prepared by the selective cleavage of the acylgroup from the corresponding compound of formula lc. This cleavage ofthe acyl group can be effected by employing standard hydrolysistechniques. For example, if R, signifies a halo-lower alkyl group suchas trifluoromethyl, cleavage of the acyl group can be carried out bysolvolysis, that is by dissolving the compound of formula lc aboveso-substituted in an alcohol, such as methanol, and heating thesolution. This cleavage can also be effected by treating the compound offormula lc with a base, for example, an organic or inorganic base inwater or in alcohol such as methanol. Suitable bases ineludetriethylamine and pyridine. If the cleavage is effected by basetreatment of the acyl derivative, it can be effected at room temperatureor at a temperature above room temperature with the reflux temperatureof the reaction medium being preferred; it is also expedient to effectthis reaction in the presence of an inert solvent such as water,alcohols, for example methanol, ethanol and the like, ethers such astetrahydrofuran, dimethylformamide, hydrocarbons such as hexane, ormixtures of these solvents, for example, methanol and water.

The compounds of formula 1 above form pharmaceutically acceptable acidaddition salts with organic or inorganic acids. Thus the compounds ofthe present invention form pharmaceutically acceptable acid additionsalts with inorganic acids such as hydrohalic acids for example,hydrochloric acid and hydrobromic acid and with organic acids such astartaric acid, citric acid, camphor-sulfonic acid, ethane sulfonic acid,toluene sulfonic acid, phthalic acid, ascorbic acid, maleic acid,succinic acid, formic acid, acetic acid and the like.

The compounds of formulae la, lb and le above as well as theirpharmaceutically acceptable acid addition salts are useful asanticonvulsant, muscle relaxant and sedative agents while the compoundsof formula Id are useful as muscle relaxant and sedative agents. Thusthe compounds of the present invention and their pharmaceuticallyacceptable salts can be material as medicaments. For example, they canbe used in the form of pharmaceutical preparations which contain them ortheir salts in ad-mixture with a pharmaceutical organic or inorganiccarrier matrial which is suitable for enteral or parenteral applicationsuch as, for example, water, gelatin, lactose, starches, magnesiumsterate, talc, vegetable oils, gum arabic, polyalkyleneglycols,Vaseline, etc. The pharmaceutical preparations can be prepared in solidform (e.g. as tablets, dragees, suppositories, capsules) or in liquidform (e.g. as solutions, suspensions or emulsions). They may besterilized and/or contain additives such as preserving, stabilizing,wetting or emulsifying agents, salts for varying the osmotic pressure orbuffers. They can also contain other therapeutically valuablesubstances.

The compounds of formula I above or their pharmaceutically acceptablesalts can be administered at dosages adjusted to individual requirementsand fitted to the pharmaceutical exigencies of the situation. Convenient pharmaceutical dosages are in the range of from about 2 mg. toabout 200 mg. per day.

The useful anticonvulsant activity of the compounds of formulae l'a, lband lc above is shown in warm blooded animals utilizing the standardantimetrazole test. This test was carried out according to the method ofEverett and Richard (J.P.E.T., 81: 402, 1944). The ED, was calculated asthe dose which would prevent convulsions in 50% of the mice tested afteradministration of 125 mg/kg of pentylenetetrazole by the subcutaneousroute. Following these test procedures 1.3-dihydro-7-hydroxyamino-l-methoxy-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one (Compound A), 1,3-dihydro-7-(N,hydroxyacetamino)-l'methoxymethyl-5-phenyl-2H-l,4-benzodiazepin-2-one (Compound B), and 1,3- dihydro-l-methoxymethyl7-( N- methoxytrifluoroacetamino)-5-phenyl-2H- l ,4benzodiazepin'2-one (Compound C) show an ED of l.57 i 0.17, 2.25 1*:0.47 and 2.8 t 0.4 mg/kg respectively, indicating that these compoundsexhibit anticonvulsant activity.

The sedative and muscle relaxant activity of the compounds of formula Iabove are shown using the stan' dard foot shock test. in this test apair of mice is confined under a 1 liter beaker placed on a grid whichpresents shock to the feet. At least five fighting episodes are elicitedin a two minute period. Pairs of mice are marked and pretreated 1 hourprior to a second shock. Logarithmic dose intervals are utilized up to amaximum of mg/kg. At the 100% blocking dose, three out of three pairsmust be blocked from fighting. The measurements are made at the doselevel at which 100% blocking is observed and the results are expressedas the dose in mg/kg (PO which blocks the fighting response for l-hour.Following these test procedures, compound A exhibits a PD of 5.0,Compound B exhibits a PD of 50, Compound C exhibits a PD of 5.0 andl,3-dihydro-7-methoxyamino-lmethoxymethyl-S-phenyl-2H- l,4-benzodiazepin-2-one (Compound D) exhibits a PD, of 100 mg/kg,indicating that these compounds possess sedative and muscle relaxantactivity.

The following examples are illustrative of the present invention. Alltemperatures are given in degrees Centigrade.

EXAMPLE 1 Preparation of l,3-dihydro-7-hydroxyamino-l-methoxymethyl-S-phenyl-2H-l ,4-benzodiazepin-2-one A mixture of 33g of (0.1 mol) ofl,3-dihydro-1- methoxymethyl-7-nitro-5-phenyl-2H-l,4-benzodiazepin-2-one, l l of tetrahydrofuran, l lof methanol, 113g (0.5 mol) of stannous chloride dihydrate and 136g (1mol) of sodium acetate trihydrate was stirred at room temperature for 6hrs. under an atmosphere of nitrogen. The inorganic salts were separatedby filtration over celite. The filtrate was evaporated and the residuewas partitioned between methylene chloride and 1N sodium hydroxidesolution. The methylene chloride layer was washed with water, dried andevaporated. Crystallization of the residue from methylene chloride/etheryielded the above-named product as light yellow crystals, mp l68l70. Foranalysis it was recrystallized from the same solvents, mp l68-l7l.

' Preparation of EXAMPLE 2 Preparation ofl,3-dihydro-7-hydroxyamino-l-methyl- S-phenyl-ZH-l ,4-benzodiazepin-2-one A mixture of l5g (0.05 mol) ofl,3-dihydro-l-methyl-7-nitro-5-phenyl-2H-l,4-benzodiazepin-2-one, 250 mlof tetrahydrofuran, 250 ml of methanol, 56g of stannous chloridedihydrate and 68g of sodium acetate trihydrate was stirred undernitrogen for 3 hours. 1 l of methylene chloride and ml of conc. ammoniawas added. The inorganic material was separated by filtration overcelite. The filtrate was washed with lN sodium hydroxide solution, wasdried over sodium sulfate and evaporated. Crystallization of the residuefrom methylene chloride and recrystallization from ethanol/methylenechloride yielded the above-named light yellow product, with mp 21 l2l3.

EXAMPLE 3 1,3-dihydro-5-(2-fluorophenyl)-7-hydroxyamino-l-methyl-2H-l,4-benzodiazepin-2-one A mixture of l6g (0.05mol) of l,3-dihydro-5-(2-fluorophcnyl)l-mcthyl-7-nitro-2H-l.4-benzodiazepin-2-one,

500 ml of tctrahydrofuran, 250 ml of methanol, 68g of sodium acetatetrihydrate and 56g of stannous chloride dihydrate was stirred undernitrogen for 6 hours. 25 ml of conc. ammonia was added and the inorganicsalts were removed by filtration through celite. The filtrate was washedwell with 21 of tetrahydrofuran. The filtrate was evaporated and thesolid residue was dissolved in ethanol/tetrahydrofuran. The solution wasagain filtered with celite and concentrated. The separated crystals werecollected to yield the above-named light yellow product. For analysis itwas recrystallized from ethanol/tetrahydrofuran, mp 228230dec.

EXAMPLE 4 Preparation of 5-(2-Chlorophenyl)-l,3-dihydro-7-hydroxyaminol-methoxymethyl-ZH- l ,4-benzodiazepin-2-one A mixture of3.6g (0.01 mol) of 5-(2-chlorophenyl)- l,3-dihydrol methoxymethyl-7-nitro-2H-l ,4- benzodiazepin-Z-one, 100 ml of tetrahydrofuran, 50 ml olmethanol, 13.6g of sodium acetate trihydrate and l l.25g of stannouschloride dihydrate was stirred under nitrogen for 5 hours. 500 ml ofmethylene chloride and [0 ml of conc. ammonia was added. The inorganicmaterial was separated by filtration. The filtrate was washed with lNsodium hydroxide solution, dried over sodium sulfate and evaporated.Crystallization of the residue from methylene chloride/ether gave theabove-named light yellow product with mp 205208 dec. For analysis it wasrecrystallized from 2-propanol/- tetrahydrofuran.

EXAMPLE 5 Preparation of l,3-dihydro-7-(N-hydroxyacetamino)-l-methoxymethyl-5phenyl-ZH-1 ,4-benzodiazepin-2- one A mixture ari'sg'raoa mol) of l ,3-dihydro-7-hydroxyaminol-methoxymcthyl-5-phenyl-2H- l ,4-benzodiazepin- 2-one, I00ml of pyridine and I5 ml of acetic anhydride was allowed to sit at roomtemperature for l6 hrs. The

reagents were evaporated, at the end azeotropically with xylene. Theresidue was dissolved in 100 ml of methanol. The solution was cooled inice-water when 100 ml of IN sodium hydroxide solution was added. Afterstanding at room temperature for 10 min, the reaction mixture wasacidified with solid carbondioxide and was extracted with methylenechloride. The extracts were dried and evaporated. Crystallization of theresidue from ether yielded the above-named yellow product with mp 205208d'ec. For analysis it was recrystallized from methylenechloride/Z-propanol.

EXAMPLE 6 Preparation of l,3-dihydro-7-( N-hydroxytrifluoroacetamino)-lmethoxy methyl-S-phenyl-ZH-l ,4-benzodiazepin-2-one 10 ml of Trifluoroacetic anhydride and 20 ml ofpyridine was added to a solution of 9.3g (0.07 mol) of1,3dihydro-7-hydroxyamino-1methoxymethyl-S-phenyl-2H-l,4-benzodiazepin-2-one in 500 ml of methylene chloride cooledto 50. Cooling was discontinued and the mixture was stirred for 5 min.When the temperature rose to 30 the reaction mixture was quenched with20 ml ofmethanol and shaken with saturated sodium bicarbonate solution.The organic phase was separated, dried and evaporated. Crystallizationof the residue from ether/petroleum ether yielded the above-named tanproduct with mp. ll 78 dec. Recrystallization from methylenechloride/methanol/ether gave the product as offwhite crystals with mpl83-l85 dec.

EXAMPLE 7 Preparation of l,3-dihydro-7-(N-methoxyacetamino)-lmethoxymethyl-Sphenyl-ZH-l ,4-benZodiazepin-2- one l.2 g (0.0l06 mollof potassidm t-butoxide was added to a solution of 3.6g (0.01 mol) ofl,3-dihydro-7-(N- hydroxyacetamino l -methoxymethyl-Sphenyl-ZH-1,4-benzodiazepin-2-one in 40 ml of dimethylformamide cooled to l0.After stirring for 10 min 1.5g (0.0106 mol) of methyliodide was addedand stirring was continued for IS min at room temperature. The solventwas partially evaporated under reduced pressure. The remaining warmsolution was diluted with water and crystallized by seeding and cooling.Seeds were obtained by previous chromatographic purification over silicagel using 20% ethylacetate in methylene chloride. The crystals werecollected and recrystallized twice from methylene chloride/ether/hexaneto yield the above-named light yellow product with mp l25l28.

EXAMPLE 8 Preparation of l,3-dihydro-l-methoxymethyl-7-(N-methoxytrifluoroacetamino )-5-phenyl-2H- l ,4- benzodiazepin-2-oneEthereal diazomethane was added to a solution of 2g (0.005 mol) ofl,3-dihydro-7-(N-hydroxy trifluoroacetamino)-lmethoxymethyl-5-phenyl-2H- l ,4-benzodiazepin-2-one in 40 ml ofmethylene chloride and 20 ml of methanol. After no more gas evolutionwas noticed (l5 min) the tions from ether/hexane yielded the above-namedproduct with mp. 110-1 12.

EXAMPLE 9 Preparation of l,3dihydro-7-methoxyamino- 1methoxymethyl-S-pheny1-2H-1,4-benzodiazepin-2*one 1 ml of triethylaminewas added to a solution of lg of1,3-dihydro-1-methoxymethyl-7-(N-methoxytrifluoroacetamino)-5-phenyl-2H-1,4-benzodiazepin-2-one in 20 ml of methanol. After refluxing for min the solvents wereremoved under reduced pressure and the residue was crystallized fromether to yield the above-named light yellow product with mp 1. The drugwas mixed with lactose and corn starch in a suitable mixer.

2. The mixture was further blended by passing through a FitzpatrickComminuting machine with a No. 1A screen with knives forward.

3. The blended powder was returned to the mixer, the tale added andblended thoroughly.

4. The mixture was filled into No. 4 hard shell gelatin capsules on aParke Davis capsulating machine.

EXAMPLE 11 Capsule Formulation Per Capsulel.3-dihydro-7-hydroxyaminolmethoxymethyl-5-phenyl-2H-1,4-benzodiazepin-Z-onc 10 mg Lactose 15 8 mg Corn Starch 37 mg Tale 5 mgTotal Weight 210 mg Procedure:

1. The drug was mixed with the lactose and corn starch in a suitablemixer.

2. The mixer was further blended by passing through a FitzpatrickComminuting machine with a No. 1A screen with knives forward.

3. The blended powder was returned to the mixer, the tale added andblended thoroughly. The mixture was then filled into No. 4 hard shellgelatin capsules on a Parke Davis capsulating machine. (Any similar typemachine may be used).

EXAMPLE ll 2 Tablet Formulation Per Tablet l,3-dihydro-7 hydroxyamino-1-methoxymethyl-S-phenyl- 2H-1,4- benzodiazepin-z-one 25.00 mg Lactose,USP 64.50 mg Corn Starch 10.00 mg Magnesium Sterate 0.50 mg Total Weight100.00 mg Procedure:

1 The drug was mixed with the lactose, corn starch and magnesiumstearate in a suitable mixer.

2. The mixture was further blended by passing through a FitzpatrickComminuting machine fitted with a No. 1A screen with knives forward.

3. The mixed powders were slugged on a tablet compressing machine.

4.'The slugs were comminuted to a mesh size (No. 16 screen) and mixedwell.

5. The tablets were compressed at a tablet weight of mg using tabletpunches having a diameter of approximately /1 inch. (Tablets may beeither flat or biconvex and may be scored if desired).

1. The drug was mixed with the: lactose, corn starch and pregelatinizedcorn starch in a suitable size mixer.

2. The mix was passed through a Fitzpatrick Comminuting machine fittedwith No. 1A screen and with knives forward.

3. The mix was returned to the mixer and moistened with water to a thickpaste. The moist mass was passed through a No. 12 screen and the moistgranules were dried on paper lined trays at F.

4. The dried granules were returned to the mixer, the calcium stearatewas added, and mixed well.

5. The granules were compressed at a tablet weight of 200 mg usingstandard concave punches having a diameter of 5/16 inch.

We claim:

1. A compound of the formula wherein R signifies lower alkyl,hydroxylower alkyl, cycloalkyl-lower alkyl wherein the cycloalkyl grouphas 3 to 7 carbon atoms, lower alkoxy-lower alkyl or diloweralkylaminolower alkyl; R signifies hydrogen or lower alkyl; R signifieshydrogen orhalogen; R signifies hydrogen or lower alkyl; R signifieshydrogen or the group COR wherein R is lower alkyl or halolower alkyl,

and the pharmaceutically acceptable acid addition salts thereof.

2. A compound of claim 1 wherein R and R are hydrogen.

3. The compound of claim 2 of the formulal,3-dihydro-7-hydroxyamino-l-methoxymethyl-5-phenyl-2H-1,4-benzodiazepin-2-one.

4. The compound of claim 2 of the formula 1,3-dihydro- 'l -hydroxyaminol -methyl-5-phenyl-2H-1 ,4- benzodiazepin-Z-one.

5. The compound of claim 2 of the formula 1,3-

I dihydro-S-(2-fluorophenyl)-7-hydroxyamino-lmethyI-ZH-l,4-benzodiazepin-2-one.

6. The compound of claim 2 of the formula 1,3- dihydro-5-(2-chlorophenyl )-7-hydroxyaminol methoxymethyl-ZH-l,4-benzodiazepin-2-one.

7. A compound of claim 1 wherein R signifies hydrogen and R signifiesthe group -COR R being lower alkyl or halo-lower alkyl.

1. A COMPOUND OF THE FORMULA
 2. A compound of claim 1 wherein R4 and R5are hydrogen.
 3. The compound of claim 2 of the formula1,3-dihydro-7-hydroxyamino-1methoxymethyl-5-phenyl-2H-1,4-benzodiazepin-2-one.
 4. The compound of claim 2 of the formula1,3-dihydro-7-hydroxyamino-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one.5. The compound of claim 2 of the formula1,3-dihydro-5-(2-fluorophenyl)-7-hydroxyamino-1-methyl-2H-1,4-benzodiazepin-2-one.
 6. The compound of claim 2 of the formula1,3-dihydro-5-(2-chlorophenyl)-7-hydroxyamino-1-methoxymethyl-2H-1,4-benzodiazepin-2-one.
 7. A compound of claim 1 wherein R4 signifieshydrogen and R5 signifies the group -COR6, R6 being lower alkyl orhalo-lower alkyl.
 8. The compound of claim 7 of the formula1,3-dihydro-7-(N-hydroxyacetamino)-1-methoxymethyl-5-phenyl-2H-1,4-benzodiazepin-2-one.
 9. The compound of claim 7 of the formula1,3-dihydro-7-(N-hydroxy-trifluoroacetamino)-1-methoxymethyl-5-phenyl-2H-1,4-benzodiazepin-2-one.10. A compound of claim 1 wherein R4 signifies lower alkyl and R5signifies the group -COR6, R6 being lower alkyl or halo-lower alkyl. 11.The compound of claim 10 of the formula1,3-dihydro-7-(N-methoxyacetamimo)1-methoxymethyl-5-phenyl-2H-1,4-benzodiazepin-2-one.
 12. The compound ofclaim 10 of the formula1,3-dihydro-1-methoxymethyl-7-(N-methoxytrifluoroacetamino)-5-phenyl-2H-1,4-benzodiazepin-2-one. 13.1,3-Dihydro-7-methoxyamino-1-methoxymethyl-5-phenyl-2H-1,4-benzodiazepin-2-one.